PROJECT SUMMARY/ABSTRACT This is an application for a K01 award for Dr. Joshua Vsquez, MD, Assistant Professor in the Division of Experimental Medicine and the Division Pulmonary and Critical Care Medicine at the University of California at San Francisco who is establishing himself as a clinician-scientist in HIV immunology. His goal is to apply his pulmonary medicine background from a clinical fellowship to study the mechanisms that underlie pulmonary inflammation and immune dysfunction in treated HIV disease. This award will provide him with the support to accomplish the following goals: (1) to characterize the pulmonary reservoir of HIV and (2) to determine whether phenotypic and functional defects persist in alveolar macrophages responsible for patrolling the alveolar- capillary barrier, despite antiretroviral therapy, particularly among those with low CD4+ T cell nadirs. To achieve these goals, he will have four co-mentors who each have unique strengths and established track records of productive scientific investigation and mentorship of research fellows. His primary mentor is Dr. Peter Hunt, the interim chief of the Division of Experimental Medicine at UCSF/Zuckerberg San Francisco General Hospital, and an internationally-recognized expert in HIV translational immunology, specifically the mechanisms and consequences of chronic inflammation during treated HIV disease. Dr. Vasquez will also work with co-mentors Dr. Joseph (Mike) McCune, a preeminent immunologist who has conducted many seminal studies in HIV pathogenesis; Dr. Clifford Lowell, Chair of Laboratory Medicine and a recognized expert on intracellular signaling pathways regulating inflammation in the innate immune system; and Dr. Laurence Huang, an internationally-recognized expert in the pulmonary complications of HIV disease. He has also engaged active collaborators who will continue to provide focused support in the areas of: HIV tissue reservoir assessment by PCR (Dr. Steven Yukl), HIV-associated tissue pathology (Dr. Zoltan Laszik), alveolar macrophage immunology (Dr. Mehrdad Arjomandi), biostatistics (Dr. Peter Bacchetti), pulmonary immunology (Dr. Prescott Woodruff), as well as mass cytometry and high dimensional computational analysis (Dr. Matthew Spitzer). As a part of this award, he will pursue additional training in translational research, immunology methods, and bioinformatics. Leveraging access to unique patient samples, he will apply existing and novel immunologic techniques to determine how alveolar macrophage programs are altered in the setting of HIV disease. The results of these studies should be widely applicable to our understanding of the tissue immunology of other common diseases and be useful to guide the development of immunomodulatory therapies targeted at myeloid cells. Ultimately, the training and research plans outlined here will support his transition from being a basic immunologist and clinical pulmonary/critical care specialist to being a translational researcher equipped with the skills to pursue an independent career focused on elucidating the fundamental principles of myeloid cell biology and informing the development of therapeutics and vaccines for infectious diseases.